Peptides as therapeutic agents or drug leads for autoimmune, hormone dependent and cardiovascular diseases

Peptides regulate most physiological processes, mainly by binding to specific receptors located on the cell surface and inducing a series of signals, neurotransmissions or the release of growth factors. There has been a rapid expansion in the use of peptides as therapeutic agents after the 1960s, but a series of unfortunate side effects present in Phase I and II clinical studies combined with their low bioavailability, led to the introduction of the idea of peptidomimetics as alternative compounds that mimic the biological activity of peptides, while offering the advantages of increased bioavailability, biostability, bioefficiency, and bioselectivity. Since then new peptides with promising in vitro results, involving the monoclonal antibody expansion, as well as the newly launched research field for novel formulations for increasing peptides' bioavailability, redirected the interest on the peptide market. In this report we will highlight three areas where the use of peptides has shown promising results, with products that are either currently used as drugs or included into Phase III clinical studies

Rationally designed cyclic analogues of luteinizing hormone-releasing hormone: Enhanced enzymatic stability and biological properties

This article describes the rational design, synthesis and pharmacological properties of amide-linked cyclic analogues of Luteinizing Hormone-Releasing Hormone (LHRH) with substitutions at positions 1 (Pro), 6 (d-Leu/d-Trp), 9 (Aze) and 10 (BABA/Acp). These LHRH analogues fulfil the conformational requirements that are known in the literature (bend in the 5–8 segment) to be essential for receptor recognition and activation. Although, they are characterised by an overall low binding affinity to the LHRH-I receptor, the cyclic analogues that were studied and especially the cyclo(1-10)[Pro1, d-Leu6, BABA10] LHRH, exhibit a profoundly enhanced in vitro and in vivo stability and improved pharmacokinetics in comparison with their linear counterpart and leuprolide. Upon receptor binding, cyclo(1-10)[Pro1, d-Leu6, BABA10] LHRH causes testosterone release in C57/B16 mice (in vivo efficacy) that is comparable to that of leuprolide. Testosterone release is an acutely dose dependent effect that is blocked by the LHRH-I receptor antagonist, cetrorelix. The pharmacokinetic advantages and efficacy of cyclo(1-10)[Pro1, d-Leu6, BABA10] LHRH render this analogue a promising platform for future rational drug design studies towards the development of non-peptide LHRH mimetics. [Display omitted] ► We designed cyclic peptide analogues of LH-RH hormone with crucial substitutions. ► The cyclic analogues were more stable in proteolysis compared to linear counterparts. ► The rationally designed cyclic analogues were studied in binding assay. ► We report the testosterone release of more potent cyclic analogue in mice